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Published on: November 16, 2011
HSP72 protects against obesity-induced insulin resistance
Jason Chung1, Anh-Khoi Nguyen, Darren C Henstridge
1Cellular and Molecular Metabolism Laboratory, Clinical Physiology, and Human Vascular Biology, Baker Heart Research Institute, Prahran, P.O. Box 6492, Victoria 8008, Australia.
Abstract:
Patients with type 2 diabetes have reduced gene expression of heat shock protein (HSP) 72, which correlates with reduced insulin sensitivity. Heat therapy, which activates HSP72, improves clinical parameters in these patients. Activation of several inflammatory signaling proteins such as c-jun amino terminal kinase (JNK), inhibitor of kappaB kinase, and tumor necrosis factor-alpha, can induce insulin resistance, but HSP 72 can block the induction of these molecules in vitro. Accordingly, we examined whether activation of HSP72 can protect against the development of insulin resistance. First, we show that obese, insulin resistant humans have reduced HSP72 protein expression and increased JNK phosphorylation in skeletal muscle. We next used heat shock therapy, transgenic overexpression, and pharmacologic means to overexpress HSP72 either specifically in skeletal muscle or globally in mice. Herein, we show that regardless of the means used to achieve an elevation in HSP72 protein, protection against diet- or obesity-induced hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance was observed. This protection was tightly associated with the prevention of JNK phosphorylation. These findings identify an essential role for HSP72 in blocking inflammation and preventing insulin resistance in the context of genetic obesity or high-fat feeding.
Insights
Heat shock protein 72 (HSP72) protects against insulin resistance. Increasing HSP72 levels in skeletal muscle prevents diet- or obesity-induced metabolic dysfunction by blocking inflammation.
Area of Science:
- Metabolic disease research
- Molecular biology
- Cellular stress response
Background:
- Type 2 diabetes is linked to reduced heat shock protein 72 (HSP72) expression and insulin sensitivity.
- Inflammatory pathways involving c-jun amino terminal kinase (JNK) contribute to insulin resistance.
- HSP72 has demonstrated in vitro ability to inhibit inflammatory signaling molecules.
Purpose of the Study:
- To investigate whether activating heat shock protein 72 (HSP72) can prevent the development of insulin resistance.
- To determine the role of HSP72 in mitigating inflammation associated with obesity and insulin resistance.
Main Methods:
- Assessed HSP72 protein levels and JNK phosphorylation in skeletal muscle of obese, insulin-resistant humans.
- Utilized heat shock therapy, transgenic overexpression, and pharmacologic methods to elevate HSP72 in mice.
- Evaluated metabolic parameters including hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance.
Main Results:
- Obese, insulin-resistant humans exhibit lower HSP72 expression and higher JNK phosphorylation in skeletal muscle.
- Elevated HSP72 levels, achieved through various methods, protected against diet- and obesity-induced metabolic dysfunction.
- Protection against insulin resistance was strongly correlated with the inhibition of JNK phosphorylation.
Conclusions:
- Heat shock protein 72 (HSP72) plays a crucial role in preventing insulin resistance.
- HSP72 activation effectively blocks inflammatory signaling pathways, thereby protecting against metabolic impairments.
- Targeting HSP72 represents a potential therapeutic strategy for managing insulin resistance in obesity and type 2 diabetes.
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